Systemic Delivery of mPEG‐Masked Trispecific T‐Cell Nanoengagers in Synergy with STING Agonists Overcomes Immunotherapy Resistance in TNBC and Generates a Vaccination Effect. Issue 32 (11th September 2022)

• Record Type: Journal Article
• Authors: Shen, Ming; Chen, Chuanrong; Guo, Qianqian; Wang, Quan; Liao, Jinghan; Wang, Liting; Yu, Jian; Xue, Man; Duan, Yourong; Zhang, Jiali
• Is Part Of: Advanced science. Volume 9:Issue 32(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-11
• Subjects: cancer stem cells -- PD‐L1 blockade -- STING agonist -- T‐cell engager -- triple‐negative breast cancer; Science -- Periodicals; 505
• DOI: 10.1002/advs.202203523
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: T‐cell engagers (TCEs) represent a breakthrough in hematological malignancy treatment but are vulnerable to antigen escape and lack a vaccination effect. The "immunologically cold" solid tumor presents substantial challenges due to intratumor heterogeneity and an immunosuppressive tumor microenvironment (TME). Here, a methoxy poly(ethylene glycol) (mPEG)‐masked CD44×PD‐L1/CD3 trispecific T‐cell nanoengager loaded with the STING agonist c‐di‐AMP (CDA) (PmTriTNE@CDA) for the treatment of triple‐negative breast cancer (TNBC) is rationally designed. PmTriTNE@CDA shows tumor‐specific accumulation and is preferentially unmasked in response to a weakly acidic TME to prevent on‐target off‐tumor toxicity. The unmasked CD44×PD‐L1/CD3 trispecific T‐cell nanoengager (TriTNE) targets dual tumor‐associated antigens (TAAs) to redirect CD8+ T cells for heterogeneous TNBC lysis while achieving PD‐L1 blockade. PmTriTNE synergized with CDA to transform the cold tumor into a hot tumor, eradicate the large established TNBC tumor, and induce protective immune memory in a 4T1 orthotopic tumor model without causing obvious toxicity. PmTriTNE@CDA shows potent efficacy in cell line‐derived xenograft (CDX) and patient‐derived xenograft (PDX) mouse models. This study serves as a proof‐of‐concept demonstration of a nanobased TCEs strategy to expand therapeutic combinations that previously could not be achieved due to systemic toxicity with the aim of overcoming TNBC heterogeneity and immunotherapy resistance. Abstract : CD44×PD‐L1/CD3 trispecific T‐cell nanoengager loaded with the STING agonist c‐di‐AMP (CDA) (PmTriTNE@CDA) shows tumor‐specific accumulation and the preferentially unmasked in response to the weakly acidic TME to avoid on‐target off‐tumor toxicity. CDA synergizes with PmTriTNE to eliminate triple‐negative breast cancer (TNBC), especially cancer stem cells (CSCs) and coordinate innate and adaptive immunity to achieve whole cancer immunity cycle cascade amplification against heterogeneous TNBC and generate a vaccination effect.